| Post transplantation diabetes mellitus (PTDM) is a well-recognized complication of solid-organ transplantation. The incidence of PTDM ranges from 2% to 53%. PTDM contributes to the risk for cardiovascular disease and infection, reducing graft and patient survival. Some factors, such as older age, obesity, and ethnicity, family history of diabetes, cadaver donor, and immunosuppressive regimen are risk markers for the development of PTDM. Recent studies have shown that Calpain10 gene, transcription factor 7-like 2 (TCF7L2) gene and zinc transporter solute carrier family 30 member 8 gene (SLC30A8) polymorphisms are associated with PTDM. However, whether the genetic polymorphisms are associated with PTDM in Chinese renal allograft recipients still remains unknown and needs further extensive investigation.The goals of this study was to investigate the incidence of PTDM, identify the risk factors and the susceptibility genes for its development in Chinese renal allograft recipients, and discover treatment strategies that lead to improved patient outcomes.In the present study, a total of 567 unrelated renal allograft recipients were recruited in this retrospective study to evaluate the incidence, risk factors of PTDM and the effect of different immunosuppressive agents such as cyclosporine (CsA) and tacrolimus (FK506) on the development of PTDM. In addition,137 patients with PTDM were enrolled to observer the clinical effect and safety of oral glucose-lowering mediations and insulin therapy. Seven single nucleotide polymorphisms (adiponectin gene SNP-45?SNP-276, CAPN10 gene SNP-19?SNP-3?SNP-63, TCF7L2 rs290487 and SLC30A8 rs13266634) were genotyped in the cohort, which consisted of 97 renal allograft recipients with PTDM (PTDM group) and 301 renal allograft recipients without PTDM (control group). The genotypes of polymorphisms were performed by allele specific polymerase chain reaction (ASPCR), PCR-restriction fragment length polymorphism (PCR-RFLP) and real-time fluorescence PCR.The results showed that the incidence of PTDM was 24.2%. Male patients had significant higher incidence of PTDM (27.4%) than female patients (17.2%). The older age (>45 years), high body weight (>65kg) and high BMI (>24 kg·m-2) at transplantation, male gender, immunosuppression with high-dose and high-concentration cyclosporine were significantly associated with PTDM in Chinese renal allograft recipients. It was showed that male sex (odds ratio=1.813,95%CI:1.160-2.834, P=0.009) and older age of> 45 years (odds ratio=2.528, 95% CI:1.706-3.746, P<0.001) denoted a higher risk of PTDM. Those who have a high BMI of>25 kg·m-2 were 1.819 times (OR=1.819,95% CI:1.203-2.750, P=0.005) more likely to develop PTDM.The incidences of PTDM in CsA-treated group and FK506-treated group were 23.1% and 29.3%, respectively (p=0.197). The FPG levels of FK506-treated group were significantly higher than CsA-treated group at 1?24 months after transplantation (p<0.05). The daily doses and blood concentrations of CsA at 1?24 months after transplantation were significantly higher in PTDM patients compared to non-PTDM patients (p<0.05).The GG genotypes in SNP-45 and SNP-276 of adiponectin gene were more common in patients with PTDM than those without PTDM (13.4% vs.4.6%, p=0.005;56.7% vs.40.9%, p=0.005). When adjusted for age, sex, body weight and BMI, the risk of the SNP-45 genotypes (OR=2.844 for GG compared to TT, p=0.016;OR=3.289 for GG compared to TG, p=0.008), SNP-276 genotypes (OR=2.168 for GG compared to TG, p=0.003) remained significant.The 1-allele frequency in SNP-19 of calpain10 gene was higher in patients with PTDM than those without PTDM (37.6% vs 29.1%, P=0.032). The G-allele frequency of SNP-43 in patients with PTDM was also higher than those without PTDM (95.4% vs 90.5%, P=0.036). The distribution of polymorphism of the SNP-63 site was not significantly different between the patients with and without PTDM (P=0.069). The 11 genotypes of SNP-19 and GG genotypes of SNP-43 in patients with and without PTDM were 12.4%,91.8% and 10.0%, 81.7%, respectively (P<0.05). There was not significant difference in allele distributions of SNP-63 between the two groups (p=0.139). After adjustments for age, sex, body weight and BMI, the effect of genotype remained significant (11 vs 22, OR=1.502,95%CI:1.016-2.347, p=0.048; 12 vs 22, OR=1.764,95%CI:1.055-2.947, p=0.030) in SNP-19 and the patients carrying genotype GG had higher risk comparison with carriers with genotype AA or GA (OR =2.190,95%CI:1.047-3.473, p= 0.044) in SNP-43. But SNP-63 was not association with PTDM.In TCF7L2 gene rs290487, the frequency of allele C and genotype CC in the patients with PTDM were higher than that in the patients without PTDM (50.5% vs 39.5%, p=0.008; 27.8% vs18.3%, p=0.039, respectively). The age-, sex-, body weight-, and BMI-adjusted OR of PTDM was 2.3 (OR=2.300,95%CI:1.196-4.425, p=0.013) for the CC genotype versus the TT genotype.There was a significant difference in SLC30A8 rs 13266634 C allelic frequency between patients with and without PTDM (57.7% vs 45.3%, p=0.003). The frequency of CC genotype in the patients with PTDM was also higher than that in the patients without PTDM (34.0% vs 23.2%, p=0.015). After adjustment for age, sex, body weight and BMI, the effect of CC genotype remains significant after multivariable logistic regression for PTDM (OR=2.108, 95%CI:1.075-4.131, p=0.044) and CC+CT genotypes conferred an independent higher risk for PTDM than did the TT genotype (OR=1.862,95%CI:1.049-3.306, p=0.034).Oral glucose-lowering mediations and insulin therapy can enhance insulin secretion and reduce the concentration of blood glucose. These therapies can also improve kidney function in PTDM patients and decrease the level of serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL). There were no obvious side effects be found in this clinical study.In conclusion, older recipient age (>45 years), high body weight (>65kg) and high BMI (>25 kg·m-2) at transplantation, male gender, family history of diabetes, cadaver donor, immunosuppressant with high-dose and high-concentration cyclosporine, GG genotypes in SNP-45 and SNP-276 of adiponectin gene, the 1-allele in SNP-19 SNP-43 and GG genotype in SNP-43 of CAPN10 gene?the C alleles in TCF7L2 rs290487 and in SLC30A8 rsl3266634 are the independent risk factors of PTDM in Chinese renal allograft recipients. Adiponectin gene?CalpainlO gene, TCF7L2 gene and SLC30A8 gene are the susceptibility gene for PTDM. The diabetogenic activity of tacrolimus was higher than cyclosporine in the present study.Lifestyle modifications (diet control and exercise), withdrawing of immunosuppressive agent can reduce the concentration of blood glucose. Oral glucose-lowering mediations and insulin therapy are effective and safe medications for PTDM.Identifying recipients at reduced risk for PTDM, taking into account the impact of independent risk factors such as age, BMI and susceptibility gene can help clinicians in planning therapeutic management of modifiable risk factors for PTDM after renal transplant. Because of the higher diabetogenic activity of tacrolimus and cyclosporine, it could be reasonable to reduce dosages in patients with several associated risk factors, although this approach has yet to be demonstrated. |
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